Obesity is a serious public health concern, associated with a number of health conditions. The National Center for Health Statistics reports that 65% of adults are considered to be overweight (pre-obese), with greater than 34% of those adults considered to be obese. The incidences of obesity have dramatically increased over the last twenty years, with the percentage of obese adults having doubled from 1980 to 2004. Children are at risk as well, with an estimated 17% of children from age 2-19 classified as obese. Medical conditions commonly associated with obesity include diabetes and high blood pressure, which may lead to cardiovascular disease, stroke, and premature mortality.
As a result, there has been an increase in demand for medications to treat pre-obesity and obesity. One type of medication that is available to treat obesity is anorectics, also known as appetite suppressants. One well-known anorectic is Fen-Phen, which was widely prescribed for weight loss in the early 1990s. Fen-Phen is a combination drug that comprises two compounds; namely, fenfluramine and phentermine. Fenfluramine acts via a serotonergic mechanism to increase a user's satiety. Phentermine has a stimulant effect, acting mainly through dopaminergic and noradrenergic mechanisms to decrease a user's appetite. Fen-Phen, although effective in the treatment of obesity, was linked to possible valvular heart disease and pulmonary hypertension in 1997. As a result, fenfluramine and the Fen-Phen combination drug were pulled from the market in 1997.
It is thought that the valvular heart disease and pulmonary hypertension associated with the use of fenfluramine and its active metabolite norfenfluramine may result from the stimulation of 5-hydroxytryptamine (5-HT) serotonin receptors. Studies have shown that, in particular, fenfluramine is a potent agonist of a particular type of 5-HT receptor, the 5-HT2B receptor, which is present in human cardiac valves. Phentermine is still available in many countries, including the United States; however, it is classified as a controlled substance due to its chemical and pharmacological similarity to amphetamines. One concern with such compounds is the high potential for abuse.
Another anorectic, which was prescribed for the short-term treatment of obesity, is phenmetrazine Phenmetrazine is reportedly a potent substrate for norepinephrine and dopamine transporters and displays stimulant properties similar to those of amphetamines. Some reports indicate that phenmetrazine has been widely abused as a recreational drug and has greater addiction potential than amphetamines. Because of phenmetrazine's high potential for abuse, it was pulled from the market.
Subsequently, phendimetrazine, a close analogue of phenmetrazine with a methyl substituent on the amine, was released onto the market as an anorectic. Recent research has suggested that phendimetrazine actually exerts its effect via conversion to phenmetrazine. See Rothman et al., Eur. J. Pharmacology 447: 51-57 (2002), incorporated herein by reference. Thus, as with phenmetrazine, phendimetrazine also has a high potential for abuse. Although it is still available for the treatment of obesity, phendimetrazine is a Class III controlled substance and there is a high likelihood of abuse of this drug.
Accordingly, there is a need for an anorectic drug that acts similarly to the aforementioned drugs on the central nervous system, but does not provide such high potential for abuse and/or does not act as an agonist of the 5-HT2B receptor. Because of their effects on the central nervous system, such compounds may be useful not only for treating obesity and pre-obesity, but also for other diseases related to the central nervous system including addiction, depression, and anxiety.